Serum cobalt and chromium concentration following total hip arthroplasty: a Bayesian network meta-analysis

The present systematic review investigated the concentration of chromium (Cr) and cobalt (Co) in serum in patients who have undergone total hip arthroplasty (THA). The first outcome of interest was to investigate the mean concentration in serum of Cr and Co using different material combinations and to verify whether their concentrations change significantly using different patterns of head and liner in THA. The second outcome of interest was to investigate whether the time elapsed from the index surgery to the follow-up, BMI, sex, and side exert an influence on the mean concentration of Cr and Co in serum in patients who have undergone THA. The following material combinations were investigated (head-liner): Ceramic-Co Cr (CoCr), CoCr-CoCr, CoCr-Polyethylene, CoCr high carbide-CoCr high carbide. Data from 2756 procedures were retrieved. The mean length of follow-up was 69.3 ± 47.7 months. The ANOVA test evidenced good comparability in age, length of follow-up, BMI, and sex (P > 0.1). In patients who have undergone THA, the mean concentration in the serum of Co ranged between 0.5 µg/L and 3.5 µg/L, and the mean concentration of Cr from 0.6 to 2.6 µg/L. The difference in the concentration of Co and Cr in serum is strictly related to the implant configuration, with the coupling CoCr-CoCr showing the highest and CoCr-Polyethylene showing the lowest concentration. Patient characteristics, BMI, sex, side and the time elapsed from the index surgery to the last follow-up did not exert a significant influence on the concentration of Co and Cr in serum in patients who have undergone total hip arthroplasty (THA).

The present systematic review investigated the concentration of Co and Cr in the serum of patients who had undergone THA. The first outcome of interest was to investigate the mean serum concentration of Cr and Co in patients who have undergone THA using different material combinations, and to verify whether their concentrations change significantly using different head and liner coupling. The second outcome of interest was to investigate whether the time elapsed from the index surgery to the follow-up, BMI, sex, and side exert an influence in the mean concentration in serum of Cr and Co. The following material combinations were investigated (head-liner): Ceramic-CoCr, CoCr-CoCr, CoCr-Polyethylene, CoCr HC -CoCr HC . It was hypothesised that patient characteristics and the time elapsed from the index surgery to the last follow-up did not exert a significant influence on the concentration of Co and Cr in serum.

Methods
Eligibility criteria. All the clinical trials investigating the concentration (µg/L) of Cr and/ or Co in serum in patients who have undergone THA were considered. Only studies which clearly stated the composition of head and/ or liner components were eligible. Reviews, opinions, letters, editorials were not considered. In vitro, computational, biomechanics, and animal studies were not eligible. Prospective studies level I to II of evidence, according to Oxford Centre of Evidence-Based Medicine 14 , were considered. Given the authors language abilities, articles in English, German, Italian, French and Spanish were eligible. Missing data on the mean serum concentration (µg/L) of Cr and Co warranted the exclusion from the present study.
Search strategy. This study compiles with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the 2020 PRISMA checklist 15 . The PICOTD algorithm was preliminary pointed out: In December 2022, the following databases were accessed: PubMed, Web of Science, Google Scholar, Embase. No time constrain was set for the search. The following matrix of keywords were used in each database to accomplish the search using the Boolean operator AND/OR: THA AND (OR hip OR arthroplasty OR replacement OR prosthesis) AND (serum OR blood OR plasma) AND (CoCr OR Cr Co OR Cr OR Co OR metal OR steel OR high carbide). No additional filters were used in the databases search.
Selection and data collection. Two authors (F. M. and R.M.) separately performed selection and data collection. The full-text of the studies which matched the topic of interest were accessed. If the full-text was not, the article was excluded. The references of the full-text articles were screened by hand by the reviewers for inclusion. In case of disagreements, a third author (N.M.) took the final decision. Data extraction. Two authors (F.M. and R.M.) independently performed data extraction in a Microsoft Office Excel spreadsheet (version 16, Microsoft Corporation, Redmond, USA). The following generalities were retrieved: first author, year, length of the follow-up, and journal of publication. The following data at baseline were collected: number of patients, women, side, mean age, and mean BMI (Kg/m 2 ). Data concerning the mean serum concentration (µg/L) of Cr and Co were extracted at last follow-up.
Assessment of the risk of bias. The risk of bias was evaluated in accordance with the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions 16 . Two reviewers (R.G. and A.B.) evaluated the risk of bias of the extracted studies independently using the risk of bias of the software Review Manager 5.3 (The Nordic Cochrane Collaboration, Copenhagen). The following endpoints were evaluated: selection, detection, performance, attrition, reporting, and other bias. Disagreements were solved by a third author (N.M.).

Synthesis methods.
The statistical analyses were performed by the main author (F.M.) following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions 17 . For descriptive statistics, mean and standard deviation were used. To evaluate baseline comparability of patient demographic, the SPSS software was used. The analysis of variance (ANOVA) was performed assuming that values of P > 0.05 indicated comparability. The STATA/MP software (Stata Corporation, College Station, Texas, USA) was used for the network meta-analysis. The analyses were performed through the STATA routine for Bayesian hierarchical random-effects model. Continuous variables were analysed through the inverse variance method with standardized mean difference (SMD) effect measure. The confidence interval was set at 0.95. Heterogeneity was assessed using χ 2 and Higgins-I 2 tests. If χ 2 > 0.05, no statistically significant heterogeneity was found. A fixed model effect was used. If χ 2 < 0.05 and Higgins-I 2 > 60% high heterogeneity was found and a random model effect was used for analysis. A multiple linear model regression analysis through the Pearson Product-Moment Correlation Coefficient (r) was used. The Cauchy-Schwarz formula was used for inequality: + 1 is considered as positive linear correlation, while and − 1 a negative one. Values of 0.1 <| r |< 0.3, 0.3 <| r |< 0.5, and | r |> 0.5 were considered to have weak, moderate, and strong correlation, respectively. The overall significance was assessed through the χ 2 test, with values of P < 0.05 considered statistically significant.

Results
Study selection. The initial databases research resulted in 3477 articles. Of them 867 were excluded as they were duplicates. A further 2579 articles were excluded as they did not match the eligibility criteria: not reporting data on the concentration in Co and/ or Cr in serum (N = 1733), study design (N = 385), not focusing on THA (N = 329), poor level of evidence (N = 84), not clearly reported the composition of head and/ or liner (N = 45), language limitations (N = 3). A further eight studies were excluded as they did not report quantitative data under the outcomes of interests. Finally, 23 studies were included: 15 nonRCTs and 8 RCTs. The results of the literature search are shown in Fig. 1.
Risk of bias assessment. The risk of bias tool of the Cochrane Collaboration was used to evaluate the risk of bias. Given the prospective nature of the included studies, the overall risk of selection bias was low to moderate. Most studies did not perform assessor blinging or gave no information on it. Therefore, the risk of detection bias was moderate to high. The overall risk of attrition and reporting biases were both low to moderate, and the risk of other bias was moderate. Concluding, the overall quality of the methodological assessment was low to moderate ( Fig. 2).    Table 1, and the patient demographic of each group is shown in Table 2.

Mean concentration of Co and Cr in serum.
The mean concentration of Co in serum ranged between 0.5 µg/L and 3.5 µg/L. The mean concentration of Cr in serum ranged between 0.6 and 2.6 µg/L. The concentration of both materials according to the different head-liner compositions is shown in Table 3.

Multiple linear regressions.
There was evidence of a weak association between BMI and the concentration of Co in serum (r = 0.3; P = 0.03). The time elapsed from the index surgery to the last follow-up, sex, and side did not evidence any statistically significant association with the concentration of Co and Cr in serum (Table 4).

Discussion
According to the main findings of the present study, the mean concentration of Co in the serum of patients who have undergone THA ranged between 0.5 µg/L and 3.5 µg/L, and the mean concentration of Cr from 0.6 to 2.6 µg/L. The difference in the concentration of Co and Cr in serum is strictly related to the implant configuration, with the coupling CoCr-CoCr showing the highest and the coupling CoCr-Polyethylene showing the lowest concentration. These results confirm our hypothesis that patient characteristics and the time elapsed from the index surgery to the last follow-up did not exert any significant influence on the concentration of Co and Cr in serum in patients who have undergone THA. Co exists in two forms: Co 2+ and Co 3+ and the absorption is mediated by the same receptor of Fe 2+36,37 . Co has an important role as a constituent of vitamin B 12 (hydroxocobalamin) 38 . Occupational exposure to Co typically happens in hard metal industry, with the inhalation of dust; in the construction industry, through skin contact with cement; in the e-waste recycling industry, from the release of Co from several electronic devices 36,39,40 . Co can be toxic for different organs due to the accumulation and the oxidative stress 36 . Co can cause a rapid and reversible decline of cardiac systolic function 41 . Co can cross the blood-brain barrier and cause peripheral and central nervous system deficit 42 . Hearing loss, optic nerve atrophy, cognitive decline, motor axonopathy, and sensitive symptoms have been documented [43][44][45] . Co inhalation is associated with the 'hard metal lung disease' 46 . Skin contact provokes contact dermatitis and it is considered an occupational disease 47 . The hematologic effect of Co is uncertain: some studies show an association between red blood cell count and haemoglobin levels and Co concentration 48,49 . Co decreases the iodine uptake by the thyroid resulting in gout and the development of hypothyroidism 50 . Exposure to Co, associated with tungsten carbide (WC-CO) can augment the risk of developing lung cancer 51,52 . The WC-CO nanoparticles generate ROS and promote cells proliferation and inflammation 53 .
Cr exists in different oxidation states from − 2 to + 6 54 . Cr enters the cells through specific transporters, and it is reduced by glutathione reductase 55 . During this process, several reactive oxygen species can be formed, including ion superoxide and hydrogen peroxide 55 . Cr is excreted by the kidneys and through bile and hair in lower proportion 56 . Cr hazard has spread given its industrial usage 57 . Because of the heavy water contamination, urban    Table 3. Mean concentration in serum of Co and Cr using different materials combination.  55,63 . Cr has toxic effects on the reproductive system 64,65 . Cr induces an increase in IGF-1 receptors, FOXO1 and an elevation in p53 expression level in kidney cells 66 . Chronic exposure can cause tubular necrosis and renal failure 66 . Contact dermatitis is common among workers in leather factories, and it is classified as an occupational disease 67 . Cr is an extremely sensitizing agent, both through inhalation and skin contact 67,68 . Cr is a genotoxic agent and is carcinogen 69 . Professional exposure can cause lung and sinonasal cancer 70 . It can also be related with gastrointestinal tract cancer 71 . Adverse reaction to metal debris (ARMD) was described after metal-on-metal (MOM) THA, caused by the corrosion of the head and neck component 72 . Metal particles induce a local inflammatory reaction that can provokes fibrosis and osteolysis 36 . ARMD includes different histological findings 73 . In metallosis, the activation of innate response induces the formation of a granuloma surrounding metal debris 74 . Aseptic lymphocytic vasculitis associated lesion is characterized by perivascular lymphocytic infiltration and lymphoid aggregates of B and T cells, similar to a type IV reaction 75 . Type I reaction is mediated by immunoglobulin 76 . Radiography is the first line investigation for the diagnosis although it is not sensitive (62-64%) 73 . Periprosthetic osteolysis or a radiodense joint effusion can be identified [77][78][79] . MRI is the most sensitive imaging to diagnose ARMD 77 . It can detect indirect signs such as wear-induced synovitis, and direct signs generated by magnetic field variation, produced by metal fragments [80][81][82] .

Materials Co (µg/L) Cr (µg/L)
Our systematic review includes the most updated articles in the present literature. 8 RCT studies were included in this review. The other studies had an overall low-moderate risk of bias. This makes our conclusion very reliable. Our study did not examine only one type of implant, but it compared ions concentrations using different materials patterns. It allows the surgeon to have a comprehensive understanding of the risks of ions related diseases when a specific type of implant is chosen. To our knowledge, this is the first systematic review that examined the association between ions concentration and the patients' characteristics. This is another step ahead for the personalised surgery.
The present study has limitations. Firstly, the retrospective nature of some studies included in our review. Patient selection was different among the included studies. Patients suffering from renal failure were not excluded in studies 8,10,20,[23][24][25][26]29,30 . The predominant mechanism of Cr and Co excretion is glomerular filtration without reabsorption 54,83 . Renal failure can lead to an accumulation of the two ions and an increase in their toxicity, but no association was found between GFR and ion levels 84,85 . It is not clear whether renal failure is a contraindication for metal-on-metal implants, but in these patients, a strict follow-up is advised 21,86,87 . It could influence the ion concentration values. It was not used a standardised method for blood sample collection. Pre-operative data were not available in two studies 19,28 . Country, region, city closeness to the factory, pollution of the ground and even the season can influence ion levels in the blood serum 88 . The diameter of the femoral head implant was not well clarified among the included studies. It is shown that a femoral head diameter greater than 36 mm is correlated with ARMD 33,89,90 .